Novel immunotherapies, notably those acting on the immune checkpoint blockade (ICB), have been shown to be efficacious in patients with carcinoma (Ansel) et al., 2015; Carbone et al., 2017) and make remarkable progress in the clinical application. Immune checkpoint blockade (ICB) increases antitumor immunity by blocking native immune regulators such as the cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 antigen (PD-1) (Migden et al., 2018; Motzer et al., 2018; Tawbi et al., 2018).
Immune checkpoint blockade describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumor immune responses. Such therapies block proteins called “checkpoints” that are made by certain immune system cells, such as T cells, and some cancer cells. These checkpoints help keep immune responses from being too strong and sometimes can keep T cells from killing cancer cells. When these checkpoints are blocked, T cells can kill cancer cells more effectively. Examples of checkpoint proteins found on T cells or cancer cells include PD-1/PD-L1 and CTLA-4/B7-1/B7-2. Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body.
Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (e.g., anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells. Checkpoint proteins, such as B7-1/B7-2 on antigen-presenting cells (APC) and CTLA-4 on T cells, help keep the body's immune responses in check. When the T-cell receptor (TCR) binds to the antigen and major histocompatibility complex (MHC) proteins on the APC and CD28 binds to B7-1/B7-2 on the APC, the T cell can be activated. However, the binding of B7-1/B7-2 to CTLA-4 keeps the T cells in the inactive state so they are not able to kill tumor cells in the body. Blocking the binding of B7-1/B7-2 to CTLA-4 with an immune checkpoint inhibitor (an anti-CTLA-4 antibody) allows the T cells to be activated and to kill tumor cells. Some immune checkpoint inhibitors are used to treat cancer.
However, current evidence indicates that single-agent immunotherapy is not effective for many patients. Innate or adaptive resistance has been observed with single-agent immunotherapy (Pitt et al., 2016; Sharma et al., 2017), underscoring the unmet need for effective, non-toxic combination treatment strategies that can improve efficacy in a broader patient population (George et al., 2018).
A number of emerging (“second-generation”) therapies incorporate CTLA-4 and PD-1 checkpoint inhibitors as a “backbone” with other immunotherapies or non-immune based strategies in synergistic combination. These include targeted therapies such as tyrosine kinase inhibitors, co-stimulatory mAbs, epigenetic modulators, vaccines, adoptive T-cell therapy, and oncolytic viruses. A number of metabolic mechanisms, such as tryptophan, arginine and purine metabolism, have also been shown to be essential for immune evasion of tumors and could serve as co-targets in immunotherapy. Among purine metabolism, purine nucleosides, such as adenosine and its primary metabolite inosine, are low molecular weight molecules that participate in a wide variety of intracellular biochemical processes. Adenosine has a short half-life (approximately 10 seconds) and is rapidly deaminated to inosine, a stable metabolite with a half-life of approximately 15 h. Events such as inflammation, hypoxia, and tissue injury have been thought to account for adenosine degradation and generation of its metabolite inosine.
Inosine is a common component of food and was previously believed to be an inactive breakdown product and, unlike adenosine, little attention has been paid to its physiological role. However, recent studies demonstrate that inosine has neuroprotective, cardioprotective and immunomodulatory effects (Hasko et al., 2004). Also, it has been recognized that adenosine can bind to adenosine receptors and initiate intracellular signaling. Adenosine acting through adenosine receptors (ARs) exerts a wide range of anti-inflammatory and immunomodulatory effects in vivo (Hasko et al., 2004). Moreover, previous studies show that inosine produces anti-inflammatory effects related to the activation of adenosine receptors, mainly the A2a and A3 receptor whose activation can contribute to the reduction of pro-inflammatory cytokines, and tissue protective effects from endotoxin-induced and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced inflammation. However, some studies demonstrate that inosine can't be used as an adenosine receptor agonist.
The immunomodulatory effects of inosine in vivo cannot be explained fully by in vitro pharmacological characterization of inosine at the A2AR (Welihinda et al., 2016). Notably, the potential function of inosine on tumor cells has not been fully elaborated. The effect of inosine on the efficacy of immune checkpoint blockades or other pharmacologically immune active agents remains unclear. Given the in vivo stability of inosine, it was previously unrecognized that inosine can amplify the anti-tumor efficacy of ICB in vivo.